MMPs/Ph协同响应的血筒素-普鲁士蓝纳米递药系统联合光热抑制RAFLS细胞增殖和迁移的研究

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中文摘要：类风湿关节炎(rheumatoid arthritis，RA)关节处于弱酸性环境，关节中RA成纤维样滑膜细胞(RA fibroblast-like syno-viocyte，RAFLS)被异常激活，分泌大量基质金属蛋白酶(matrix metalloproteinases，MMPs)，细胞膜上CD44 受体蛋白被特异性上调。血筒素(xuetongsu，XTS)是土家族药物血筒中抑制RAFLS增殖的主要活性成分，因靶向性差限制了其开发利用。该研究构建了一种可靶向CD44 的仿生XTS-普鲁士蓝纳米(Prussian blue nanoparticles，PB NPs)载药递送系统THMPX NPs。THMPX NPs表面有透明质酸(hyaluronic acid，HA)和三聚甘油单硬脂酸酯(triglycerol monostearate，TGMS)-3-氨基苯硼酸(3-amino-benzeneboronic acid，PBA)长链(PBA-TGMS)修饰。炎性 RAFLS 中过表达的 MMPs 和 H+可协同切割纳米粒表面的 PBA-TGMS，从而暴露HA与CD44 相互作用，使THMPX NPs在RAFLS中高度富集，近红外光照射后产热并释放XTS，抑制RAFLS细胞增殖和迁移。表征发现THMPX NPs为形态均一的立方形，粒径为(190。3±4。7)nm，平均电位在(-15。3±2。3)mV，近红外光照射 5 min温度可达 41。5℃，释药呈现MMPs和H+敏感性;生物安全性考察发现THMPX NPs溶血率小于 4%，对正常的RAW264。7 和HFLS无细胞毒性;体外摄取实验表明THMPX NPs有明显的RAFLS靶向性;自由基清除实验发现THMPX NPs有优异的自由基清除能力，可清除RAFLS中的活性氧;cell counting kit-8 和划痕实验表明THMPX NPs显著抑制RAFLS活力和迁移能力。该研究为开发抗RA中药民族药创新纳米靶向药物提供了思路。

外文标题：MMPs/pH synergically responsive XTS-Prussian blue nanoparticles inhibiting proliferation and migration of RAFLS assisted with laser irradiation

外文摘要：Rheumatoid arthritis(RA)is a condition in which the joints are in a weakly acidic environment.In RA,RA fibroblast-like synoviocytes(RAFLS)in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs),and the receptor protein CD44 on the cell membrane is specifically upregulated.Xuetongsu(XTS),an active ingredient in the Tujia ethnomedicine Xuetong,is known to inhibit the proliferation of RAFLS.However,its development and utilization have been limited due to poor targeting ability.A biomimetic XTS-Prussian blue nanoparticles(PB NPs)drug delivery system called THMPX NPs which can target CD44 was constructed in this study.The surface of THMPX NPs was modified with hyaluronic acid(HA)and a long chain of triglycerol monostearate(TGMS)and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS).The overexpressed MMPs and H+in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles,exposing HA to interact with CD44.This allows THMPX NPs to accumulate highly in RAFLS,and upon near-infrared light irradiation,generate heat and release XTS,thereby inhibiting the proliferation and migration of RAFLS.Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190.3±4.7)nm and an average potential of(-15.3±2.3)mV.Upon near-infrared light irradiation for 5 min,the temperature of THMPX NPs reached 41.5℃,indicating MMPs and H+-triggered drug release.Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264.7 and human fibroblast-like synoviocytes(HFLS).In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS.Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs,capable of removing reactive oxygen species in RAFLS.Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS.This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.

外文关键词：

rheumatoid arthritis(RA)RA fibroblast-like synoviocytesXuetongsuPrussian bluehyaluronic acidmatrix metal-loproteinases(MMPs)/pH sensitivity

作者：

邓雅思、谌鑫阳、龙梦婷、郑豪、李斌、王炜、余黄合

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作者单位：

湖南中医药大学药学院创新药物研究所中药与民族药创新与发展国际实验室,湖南长沙 410208

关键词：

类风湿关节炎类风湿关节炎成纤维样滑膜细胞血筒素普鲁士蓝透明质酸 MMPs/pH协同响应

基金：

国家自然科学基金国家自然科学基金国家自然科学基金湖南省自然科学基金湖南省教育厅优秀青年项目湖南省中医药局科研项目湖南中医药大学优秀青年项目湖南省药学一流建设学科建设项目湖南省中医药民族医药国际联合实验室开放基金湖南省科技人才托举工程项目长沙市杰出创新青年培养计划湖南省大学生研究性学习和创新性实验计划湖南中医药大学研究生科研创新项目

项目编号：

8220476682174078820741222023JJ4049021B0394B20230552022022022GJSYS022023TJ-X71kq2306021S2022105410502022CX88

出版年：

2024

DOI：

10.19540/j.cnki.cjcmm.20240304.303

中国中药杂志

中国药学会

中国中药杂志

CSTPCD北大核心

影响因子：1.718

ISSN：1001-5302

年,卷(期)：2024.49(11)